Relationships between local and global mechanisms of sleep apnea, Alzheimer's disease biomarkers, and memory impairment in cognitively asymptomatic older adults

无认知症状老年人睡眠呼吸暂停、阿尔茨海默病生物标志物和记忆障碍的局部和整体机制之间的关系

• 批准号: 10625981
• 负责人: BRYCE A. MANDER
• 金额: $ 12.73万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625981
• 关键词: Acoustic Stimulation; Address; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Apnea; Atrophic; Biological Markers; Brain; Breathing; Cephalic; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Cognitive; Dementia; Development; Differential Diagnosis; Disease Progression; Elderly; Electroencephalography; Epidemiology; Episodic memory; Functional disorder; Funding; Future; Geriatric Psychiatry; Goals; Hippocampus; Human; Hypoxemia; Impaired cognition; Intervention; Intervention Studies; Knowledge; Link; Magnetic Resonance Imaging; Magnetism; Measures; Medial; Memory; Memory Loss; Memory impairment; Mentors; Methodology; Methods; Molecular; Monitor; Motor Skills; Nerve Degeneration; Neurodegenerative Disorders; Obstructive Sleep Apnea; Onset of illness; Parietal; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Perforant Pathway; Physiological; Play; Population; Positron-Emission Tomography; Prevalence; Preventive treatment; Process; Research; Research Activity; Research Personnel; Research Proposals; Resolution; Resources; Risk; Risk Reduction; Role; Severities; Sleep; Sleep Apnea Syndromes; Sleep Deprivation; Sleep Disorders; Sleep Fragmentations; Sleep disturbances; Structure; Temporal Lobe; Training; Treatment Efficacy; Work; age related; candidate identification; career; certificate program; clinically relevant; density; entorhinal cortex; epidemiology study; indexing; memory consolidation; memory encoding; neuroimaging; novel; pharmacologic; positive airway pressure; pre-clinical; procedural memory; programs; sleep spindle; standard of care; symptomatology; tau Proteins; ultra high resolution; β-amyloid burden

Project Summary/Abstract Epidemiologic evidence has established obstructive sleep apnea (OSA) as a risk factor for Alzheimer’s disease (AD). However, the mechanisms of this increase in AD risk remain unclear. Three potentially AD-relevant clinical features of OSA include severity of hypoxemia, global sleep fragmentation, and local deficits in memory-relevant sleep oscillations, i.e. slow waves and sleep spindles. These clinical features of OSA have been independently linked to amyloid and tau burden and accumulation, medial temporal lobe (MTL) degeneration, and MTL- dependent memory impairment—all hallmark biomarkers of AD. However, it remains unclear how each of these features relate to AD pathophysiology or MTL-dependent memory decline in patients with OSA. The overarching research objective of this proposal is to address these unknowns. The proposed specific aims are to determine whether distinct global and local OSA features are associated with 1) cortical amyloid burden, 2) MTL tau burden, and 3) degeneration of specific MTL brain circuits supporting multiple forms of memory known to depend on sleep and be vulnerable to AD pathophysiology. The proposed aims will be supported by leveraging existing resources, and collecting high density electroencephalography (hdEEG, 256 channels) sleep recordings in cognitively normal older adults (60-85 years) undergoing positron emission tomography (PET) to assess amyloid and tau burden, as well as ultrahigh resolution magnetic resonance imaging (uhr-MRI) of MTL structure. The proposed study will therefore capitalize on an opportunity to examine how OSA relates to AD pathological burden, MTL structure and function, and memory in an unprecedented level of detail and breadth. This is congruent with both my short and long-term career goals. Specifically, I plan to generate research proposals seeking funding to uncover the impact of distinct forms of sleep disturbance on circuit and molecular mechanisms of AD pathogenesis in humans. This will support my efforts to establish a clinical research program evaluating i) the contribution of sleep disturbance to the onset and progression of various forms of neurodegenerative disease across clinical stages, ii) the utility of sleep-based biomarkers to predict dementia onset and aid differential diagnosis between dementias, and iii) the utility of targeted sleep-based interventions to arrest cognitive decline associated with AD and related dementias. This research proposal and my long-term career goals are supported by my training plan overseen by my mentoring team which includes experts in hdEEG, uhr-MRI, MTL-dependent memory circuit function, PET methods in the context of aging and AD—including amyloid and tau PET, clinical aspects of sleep disorders, geriatric psychiatry, and neurodegenerative disease, and clinical trial design and implementation in the context of sleep disorders and AD. The proposed training plan includes structured mentoring on each of these topics and participation in a clinical research certificate program, as well as a course focused on clinical trials in AD. By establishing this research program, I hope to develop sleep-based approaches to reduce risk, delay onset, and slow progression of dementia and age-related cognitive decline.

项目摘要/摘要 流行病学证据已建立阻塞性睡眠呼吸暂停（OSA）作为阿尔茨海默氏病的危险因素 （广告）。但是，AD风险增加的机制尚不清楚。三个潜在的与广告相关的临床 OSA的特征包括低氧血症的严重程度，全球睡眠碎片化和本地定义与内存相关的定义 睡眠振荡，即缓慢的波浪和睡眠纺锤体。 OSA的这些临床特征是独立的 与淀粉样蛋白和Tau Burnen链接以及积累，媒体临时叶（MTL）变性和MTL- 依赖记忆障碍 - 所有标志性的AD生物标志物。但是，尚不清楚这些如何 OSA患者的AD病理生理学或MTL依赖性记忆下降有关的特征。总体 该建议的研究目标是解决这些未知数。拟议的具体目的是确定 不同的全球和本地OSA特征是否与1）皮质淀粉样蛋白Burnen相关，2）MTL Tau Burnen， 3）特定MTL脑电路的变性，支持多种形式的记忆已知依赖的记忆 睡眠，容易患AD病理生理学。提出的目标将通过利用现有 资源，并收集高密度脑电图（HDEEG，256个频道）睡眠记录 认知正常的老年人（60-85岁）接受正电子发射断层扫描（PET）以评估淀粉样蛋白 MTL结构的Tau Burnen以及超高分辨率磁共振成像（UHR-MRI）。这 因此，拟议的研究将利用一个机会来检查OSA与AD病理学的关系 Burnen，MTL的结构和功能，以及以空前的细节和广度水平的记忆。这是 与我的短期和长期职业目标都一致。具体来说，我计划制定研究建议 寻求资金来发现不同形式的睡眠障碍对电路和分子机制的影响 人类的AD发病机理。这将支持我为建立评估临床研究计划的努力i） 睡眠障碍对各种形式的神经退行性疾病的发作和进展的贡献 跨临床阶段，ii）基于睡眠的生物标志物预测痴呆发作和有助于差异的实用性 痴呆症和iii之间的诊断）靶向睡眠干预措施的效用以阻止认知能力下降 与AD和相关痴呆症相关。这项研究建议和我的长期职业目标得到了支持 通过我的心理团队监督的培训计划，其中包括HDEEG，UHR-MRI，MTL依赖的专家 记忆电路功能，衰老和AD的宠物方法 - 包括淀粉样蛋白和tau PET，临床 睡眠障碍，老年精神病学和神经退行性疾病以及临床试验设计的各个方面 在睡眠障碍和AD的背景下实施。拟议的培训计划包括结构化 指导这些主题中的每一个并参与临床研究证书计划，以及课程 专注于AD的临床试验。通过建立该研究计划，我希望开发基于睡眠的方法 为了降低风险，延迟发作以及痴呆症的发展缓慢和与年龄有关的认知能力下降。

项目成果

Local Sleep and Alzheimer's Disease Pathophysiology.

• DOI: 10.3389/fnins.2020.525970
• 发表时间: 2020
• 期刊: Frontiers in neuroscience
• 影响因子: 4.3
• 作者: Mander BA

Older adults at greater risk for Alzheimer's disease show stronger associations between sleep apnea severity and verbal memory.

患有阿尔茨海默病风险较高的老年人表现出睡眠呼吸暂停严重程度与言语记忆之间更强的关联。

• DOI: 10.21203/rs.3.rs-3683218/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Lui,Kitty;Dave,Abhishek;Sprecher,Kate;Chappel-Farley,Miranda;Riedner,Brady;Heston,Margo;Taylor,Chase;Carlsson,Cynthia;Okonkwo,Ozioma;Asthana,Sanjay;Johnson,Sterling;Bendlin,Barbara;Mander,Bryce;Benca,Ruth
• 通讯作者: Benca,Ruth

Sleep Disturbance Forecasts β-Amyloid Accumulation across Subsequent Years.

• DOI: 10.1016/j.cub.2020.08.017
• 发表时间: 2020-11-02
• 期刊: Current biology : CB
• 作者: Winer JR;Mander BA;Kumar S;Reed M;Baker SL;Jagust WJ;Walker MP
• 通讯作者: Walker MP

The Effects of Daytime Psilocybin Administration on Sleep: Implications for Antidepressant Action.

• DOI: 10.3389/fphar.2020.602590
• 发表时间: 2020
• 期刊: Frontiers in pharmacology
• 影响因子: 5.6
• 作者: Dudysová D;Janků K;Šmotek M;Saifutdinova E;Kopřivová J;Bušková J;Mander BA;Brunovský M;Zach P;Korčák J;Andrashko V;Viktorinová M;Tylš F;Bravermanová A;Froese T;Páleníček T;Horáček J
• 通讯作者: Horáček J

Self-reported sleep in relation to risk of dementia a quarter of a century later at age 90+: The 90+ Study.

四分之一世纪后 90 岁时自我报告的睡眠与痴呆风险的关系：90 年研究。

• DOI: 10.1080/15402002.2022.2148668
• 发表时间: 2023
• 期刊: Behavioral sleep medicine
• 影响因子: 3.1
• 作者: Melikyan,ZaruiA;Kawas,ClaudiaH;Paganini-Hill,Annlia;Jiang,Luohua;Mander,BryceA;Corrada,MaríaM
• 通讯作者: Corrada,MaríaM